Bloom Syndrome
Diseases

Author: Giulia De Lio
Date: 10/02/2014

Description

What is Bloom Syndrome?

Bloom Syndrome (in the literature, often abbreviated BS), also known as Bloom–Torre–Machacek syndrome is a rare autosomal recessive disorder characterized by short stature and predisposition to the development of cancer. Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive homologous recombination. The condition was discovered and first described by New York dermatologist Dr. David Bloom in 1954.

Epidemiology

Bloom syndrome is a rare disorder, with 265 cases reported in the Bloom's Syndrome Registry through 2009. The exact incidence is unknown. It has been reported in a variety of ethnic groups. However, it is more common in the Eastern European Jewish (Ashkenazi) population (about 25 percent of the affected families in the Bloom syndrome registry), with a prevalence of approximately 1:48,000. Parental consanguinity is common.

Bloom syndrome, 2013

Presentation

People with Bloom syndrome have low birth weight and length. They remain much shorter and thinner than others in their family, growing to an adult height of less than 5 feet.
Individuals with this disorder often have a high-pitched voice and distinctive facial features including a long, narrow face; a small lower jaw; a large nose; and prominent ears.
Affected individuals usually develop dilated blood vessels and reddening in the skin, particularly in response to sun exposure. These changes typically appear as a butterfly-shaped patch of reddened skin across the nose and cheeks. The skin changes may also affect the hands and arms.
Other features affecting some people with Bloom syndrome include learning disabilities, an increased risk of diabetes, chronic obstructive pulmonary disease (COPD), and recurrent infections of the upper respiratory tract, ears, and lungs during infancy. Men with Bloom syndrome usually do not produce sperm, and as a result are unable to father children (infertile). Women with the disorder generally have reduced fertility and experience menopause earlier than usual.

Bloom syndrome, 2010

Medical complications

Lower urinary tract obstruction in men: Several men have had a so-far poorly characterized urethral or bladder neck obstruction, resulting in death in two.
Fertility: Men with BSyn appropriately examined have had azoospermia or severe oligospermia. Women with BSyn, although often fertile, enter menopause prematurely. Eleven women with BSyn followed in the Registry have become pregnant at least once; seven of them have been delivered of a total of eleven healthy babies of normal.
Immunodeficiency: The concentration of one or more of the plasma immunoglobulins is usually abnormally low. Delayed hypersensitivity is undetected by the standard testing method.
Infections: Repeated bouts of otitis media and pneumonia that respond promptly and well to antibiotics occur throughout infancy and early childhood in at least 20% of persons with BSyn. Because the frequency of these infections does not correlate well with the severity of the immunodeficiency, and because G-ER (Gastroesophageal reflux) is so common (whenever it has been tested for appropriately in BSyn), they are more readily attributable to the G-ER.
Chronic obstructive pulmonary disease: Chronic bronchitis and bronchiectasis are common, and pulmonary failure has been the cause of death in five persons.
Diabetes mellitus: Although the diabetes mellitus of BSyn has as yet not been well characterized, it resembles the typical adult-onset type except for an exceptionally early age of onset. Diabetes has been diagnosed in 47 of 272 persons in the Registry (17.7%) at a mean age of 26.6 years (range 4-45 years). Although most of the cases have been mild, 16 have required insulin, and retinopathy has developed in two.
Abnormalities in insulin release and glucose tolerance have been detected in the eight healthy children (age 9 months to 13 years) and the three healthy young adults with BSyn (ages 22, 28, and 28 years) appropriately studied.
Feeding problems: These are prominent in the majority of newborns, infants, and young children, the child with BSyn very characteristically showing a seeming lack of interest in nursing, and then eating. Surprisingly, in an occasional infant with BSyn, nursing and then eating is completely normal. Because gastroesophageal reflux (G-ER) of severe degree has been demonstrable in the few young infants appropriately examined, it is the hypothesis of the authors that this is a major feature of BSyn, and the most probable basis for both the repeated bouts of middle ear and lung infections, via repeated micro-aspirations of gastric contents, and the wasted appearance of infants and young children.
Skin lesions: The skin at birth and during early infancy appears normal, but, typically following sun exposure during the first or second year of life, a red sun-sensitive skin lesion appears on the nose and cheeks, sometimes faintly also on the dorsa of the hands and forearms. This lesion varies in severity and extent among affected individuals; in some the lesion is minimal. In severe cases, the lesion can be bright red and can extend onto adjacent areas. Loss of the lower eyelashes and blister and fissure formation of the lower lip are common, the latter often becoming particularly bothersome and difficult to treat.
Cancer: Cancer is the most frequent medical complication in BSyn and the most common cause of death. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity. Persons with Bloom's syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 25 years old.
Myelodysplasia: This heterogeneous group of disorders has been diagnosed in 22 persons in the Registry at a median age of 23.1 years (range 3-47), and it has progressed to leukemia in at least six. In all but two, the myelodysplasia had been preceded by some form of cancer for which chemotherapy and/or radiotherapy had been administered.

Bloom's Syndrome, 2006

What genes are related to Bloom syndrome?

Bloom syndrome (BS) is an autosomal recessive chromosomal instability disorder that is caused by mutations in the BLM gene at 15q26.1. Today, more than 60 different BS-causing mutations of BLM have been detected. It is interesting to show that in the distant past time this gene had been transmitted through perfectly healthy people for untold numbers of generations.
This gene encodes a RecQ helicase, called the Bloom syndrome protein (Blm) that helps maintain the stability of DNA when the DNA duplexes are unwound during recombination repair and replication. A significant increase in gene cluster instability and sister chromatid Exchange (homologous recombination associated with crossover) is seen during mitotic recombination in patients with BS. Thus, Blm is believed to function primarily as an antirecombinase, mainly by acting as a Holliday junction dissolvase. It also interacts with other molecules involved in the sensing and repair of DNA damage.

Molecular genetics of Bloom's syndrome, 1996

Overwiew about the DNA helicase

Human cells are exposed to various physical and chemical DNA-damaging agents causing tens of thousands of DNA lesions in the genome of a single cell per day. In the absence of repair mechanisms, cells are prone to cancerous processes or cell death. The most severe form of DNA lesion is the double-stranded break (DSB), which is repaired via complex biochemical pathways. Homologous recombination (HR)-based repair mechanisms enable the cell to repair DSBs in an error-free manner. Bloom's syndrome RecQ-family DNA helicase (BLM), one of the human RecQ-family helicases, is a key player in HR-based repair processes.
One role of RecQ helicases is to function as part of the S-phase checkpoint, a surveillance mechanism for checking the accurate replication of DNA and the removal of DNA damage.

The structure

RecQ enzymes have three conserved domains that are commonly found in most helicases of this family: the core helicase domain, the RecQ-C-terminal (RQC) domain, and the helicase-and RNaseD-like-C-terminal (HRDC) domain. The helicase domain is present in all RecQ enzymes, while the RQC and∕or HRDC domains are missing in some representatives of the family. In addition, RecQ enzymes vary greatly in the length of their N- and C-terminal domains that flank the presumed catalytic core. These flanking domains are involved in heterologous protein interactions, in the regulation of protein subcellular localization, in directing oligomerization, or in conferring additional enzymatic activities.

The core domain

The core helicase domain is characterized by the presence of seven conserved motifs (I, Ia, II, III, IV, V, VI) that are present in all superfamily 1 and 2 (SF1 and SF2) helicases, and has a total size of approximately 300–450 amino acids.
These motifs are required for the enzyme to bind NTP and couple the energy derived from NTP hydrolysis to the process of nucleic acid unwinding. The determination of crystal structures of various helicases of the SF1 and SF2 family has shown that these motifs form the core of two RecA-like domains that serve as the ATP-driven “motor” of the helicase.

RQC domain

The second most highly conserved domain in RecQ helicases is the RQC domain. It is present in all RecQ enzymes with the exception of human RECQ4 and its orthologs. This domain is unique to RecQ enzymes and can be divided into two subdomains; a Zn2+-binding domain and a so-called winged helix (WH) domain. The Zn2+-binding domain is characterized by a pair of antiparallel α-helices and four Cys residues that are needed to coordinate a single Zn2+ atom.

HRDC domain

The third conserved region of RecQ helicases derives its name from its similarity with the C-terminal region of the RNaseD protein. For this reason, it is called the helicase-and-RNaseD-like-C-terminal domain. The HRDC region is much less well conserved than the helicase and RQC domains among RecQ helicases. Moreover, it is also absent from several RecQ enzymes. For example, among the five human RecQ helicases, only BLM and WRN possess a recognizable HRDC domain, which is located toward the C-terminus. Structural and biochemical studies confirmed that the HRDC domain plays a crucial role in differentiating the activity and functions of the various RecQ homologs.

The Bloom’s Syndrome Gene Product Is a 3′-5′ DNA Helicase, 1997

Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)

Protein Aminoacids Percentage Helicase and Top3

Mechanism

The proper function of RecQ helicases requires the specific interaction with topoisomeraseIII (Top 3). Top 3 changes the topological status of DNA by binding and cleaving single stranded DNA and passing either a single stranded or a double stranded DNA segment through the transient break and finally religating the break. The interaction of RecQ helicase with topoisomerase III at the N-terminal region is involved in the suppression of spontaneous and damage induced recombination and the absence of this interaction results in a lethal or very severe phenotype.

RecQ helicases: multiple structures for multiple functions?, 2009

Diagnosis

Clinical Diagnosis

Bloom’s syndrome should be considered in the following:

An individual with unexplained, severe intrauterine growth deficiency that persists into infancy, childhood, and adulthood
An unusually small, but roughly normally proportioned individual with the appearance after sun exposure of an erythematous skin lesion in the “butterfly area” of the face
An unusually small individual who develops cancer

Testing

The clinical diagnosis of, or suspicion of, BSyn can and must be confirmed by cytogenetic and/or molecular analysis of BLM, the gene in which mutations are known to cause BSyn. A sister chromatid enchange (SCE) analysis has become the standard test by which the clinical diagnosis of BSyn is confirmed.

Cytogenetic analysis: The diagnosis of BSyn can be confirmed or ruled out by analysis of any cell type that can be cultured in vitro. The most commonly examined cells are blood lymphocytes in short-term culture; cultured skin fibroblasts and exfoliated fetal cells can also be studied.

The cytogenetic features of BSyn cells in mitosis are increased numbers of the following:

Chromatid gaps, breaks, and rearrangements
Sister-chromatid exchanges (SCEs); a mean of 40-100 per metaphase (vs. <10 in controls). A greatly increased frequency of SCEs is demonstrable in BSyn cells allowed to proliferate in a medium containing 5’bromo-2’-deoxyuridine (BrdU). BSyn is the only disorder in which such evidence of hyper-recombinability is known to occur. In an individual with BSyn the mean and range of SCEs per metaphase are higher in lymphocytes than in fibroblasts, but the differences from controls in both types of cells are so great that interpretation of findings is not a problem.

Molecular Genetic Testing

Gene: BLM is the only gene in which mutations are known to cause BSyn. Mutations in BLM have been identified in the vast majority of persons with BSyn who have been appropriately tested. There are very few instances of affected individuals in whom BLM mutation(s) were not identified; these instances probably were attributable to technical limitations.